A comparison of narcotic analgesics with neuroleptics on behavioral measures of dopaminergic activity.

Because of many practical difficulties which are encountered in obtaining direct evidence for the involvement of brain neurotransmitters in the action of narcotic drugs, several indirect procedures are often employed. One such method is to compare on the same measures of drug action the narcotic drugs with a non-narcotic drug having a known mechanism of action. Haloperidol is a prototype non-narcotic drug which blocks dopamine receptors and many of its actions are believed to be associated with this receptor blockade. In this paper we compare various actions of haloperidol or other neuroleptics with morphine or other narcotic analgesics using the same testing parameters. We hope that such a comparison would evaluate the role of dopamine receptors in narcotic action and narcotic dependence. This discussion is limited only to the behavioral measures as a comparison of neurochemical measures was recently reviewed in another paper (1).     

The effects of narcotic analgesics and narcotic antagonists on ganglionic transmission in the rat.

The effects of narcotic analgesics, narcotic-antagonist analgesics and narcotic antagonists on ganglionic transmission in the superior cervical ganglia of the rat were studied $\text{in}$$\text{vivo}$ and $\text{in}$$\text{vitro}$. $\text{In}$$\text{vivo}$ administration of morphine, meperidine, methadone, pentazocine or naltrexone blocked ganglionic transmission. Levorphanol, cyclazocine, nalorphine and naloxone had no effect on ganglionic transmission in this procedure. $\text{In}$$\text{vitro}$ studies confirmed the $\text{in}$$\text{vivo}$ results with the exception of levorphanol, cyclazocine and nalorphine, which were also found to block ganglionic transmission $\text{in}$$\text{vitro}$. In both preparations, naloxone did not antagonize the effect of morphine, suggesting that the effects of morphine and the other opiates were nonspecific. Similar potency of $\text{d}$- and $\text{l}$-isomers of pentazocine and cyclazocine support this conclusion. The observation that naltrexone blocked ganglionic transmission, but the other pure narcotic antagonist, naloxone, was inactive is somewhat unique to this test procedure and possibly significant.     

Action of opiate peptides and narcotic analgesics on the cerebral cortex

The chronic experiments on freely moving cats have shown that the opiate peptides, FK33--824 (Tyr--D--Ala--Gly--MePhe--Met(o)--ol) and tetrapeptide (Tyr--D--Ala--Gly--Phe--NH2), as well as the narcotic analgesics, morphine, phentanyl and pentazocine in doses close to analgesic ones, suppress the recovery cycles of primary responses (PR) in the second somatosensory and associative zones of the brain cortex, recorded at paired stimulation of the fibres of thalamo-cortical radiation (TCR). In larger doses these agents slightly increase PR recorded at single stimulation of TCR, provoke the convulsive discharges on EEG and motor excitation of the animals. Naloxon eliminates all the mentioned effects of the tested opiate peptides and narcotic analgesics.     

Ionization constants and thermodynamic parameters of histidine and derivatives

The pK_a values for the proton dissociation of carboxyl, imidazolium, and ammonium groups for histidine and ten of its derivatives were determined electrometrically at seven temperatures in the range 10–40°C. The ΔH and ΔS values were estimated from the temperature dependence of the dissociation constants of histidine and its derivatives. These results and the pK_a values compared in terms of inductive effect suggest an ion-dipole interaction between the protonated amino group and the unprotonated imidazole ring. The charge and the solvation effects of the neighboring groups are the main factors that determine the imidazole group pK_a in histidine and its studied derivatives. The N^τ-H tautomer is favored over the N^π-H by 1.6 kcal/mol, indicating that the inductive substituent effect at position 4 of the imidazole ring is the major component in determining this tautomeric preference.     

Effect of narcotic analgesics on excitatory transmission in the spinal cord]

As demonstrated on nonanesthetized curare-immobilized spinal cats morphine, promedol and fentanyl failed to alter the amplitude of induced potentials in the ventro-lateral columns of the lumbar spinal cord, evoked by a single or repetitive stimulation of the cutaneous or pelvic nerves. In some experiments the same drugs inhibited the nerurons of the posterior horns of the spinal cord activated by the nociceptive stimulation of the peripheral receptors in intraarterial administration of bradykinin. It is suggested that a spinal component was involved in the action of hypnotic analgetics.     

Ionization constants of weak acids and bases in organic solvents

A discussion of the influence of organic solvents on pKa values is presented. Enthalpy and entropy of ionization in organic solvents are compared with aqueous systems. The impact of the solvent on the ionization constants is interpreted based on the free energy of transfer applied to all particles involved in the ionization reaction of acids and bases, and the concept of the 'medium effect' on these species. The limitation of Born's approach (which takes into account only electrostatic effects on the ionization equilibrium) is demonstrated and the importance of solute-solvent interactions on the change of the pKa values emphasized.     

The effects of morphine and various narcotic antagonist type analgesics on body temperature in rats

ED50s were determined for morphine, nalorphine, butorphanol and pentazocine induced hyperthermia in rats. Morphine produced a significant hyperthermia with the doses of 5–160 mg.kg in rats. The peak hyperthermic effect was found 1 hr after 5–20 mg/kg doses of morphine. Nalorphine, butorphanol and pentazocine produced biphasic effects on rectal temperature. Initially they produced a dose-dependent hyperthermia and later hypothermia. In a comparison of the hyperthermic ED50's of morphine, nalorphine, butorphanol and pentazocine it was found that butorphanol is more active than the others (ED50s were 4.7, 4.3, 0.54 and 11.5 mg/kg respectively). The narcotic antagonist naloxone significantly inhibited both morphine and antagonist type analgesic induced hyperthermia. These results suggests that a different mechanism(s) is involved in the hyperthermic actions of antagonist type analgesics and agonist drugs.     

The doctor's dilemma: opiate analgesics and chronic pain

Opiates are utilized routinely and effectively as a short-term analgesic treatment for a variety of acute pain conditions such as occur following trauma, and for patients with painful terminal diseases such as cancer. Because opiate analgesics are highly addictive substances, their use in the treatment of chronic nonmalignant pain remains controversial.     

Continuous narcotic infusions for relief of postoperative pain.

Relief of acute pain after surgery or trauma is still inadequate in many centres, most patients being treated with intermittent intramuscular injections of narcotic analgesics. Over the past three years continuous intravenous narcotic infusions have been used at this hospital to treat postoperative pain; recently a system has been devised whereby an hourly dose is given and the dispenser recharged every hour. The method used is cheap and reliable, and signs of overdosage may be easily checked by nursing staff. Side effects rarely occur. Fifty patients who had received intravenous infusions after undergoing major abdominal surgery were sent a questionnaire to assess postoperative pain, and the results were compared with those from 50 matched controls who had received intramuscular injections. Of those who replied, only four patients who had received the infusion had found the pain distressing compared with 13 controls. Continuous narcotic infusions are most effective in relieving postoperative pain and may be given cheaply and reliably.     

Inhibition of ganglionic transmission by narcotic analgesics; an effect antagonized by naloxone, nalorphine and calcium

Methadone, azidomorphine, oxycodone and fentanyl inhibit synaptic transmission in isolated sympathetic ganglia of the frog and rat, just as did morphine and pethidine in our previous investigations. This inhibitory effect can be antagonized not only by naloxone and nalorphine but also by increasing calcium concentration of the perfusion fluid of the ganglia. The inhibitory effect on transmission of narcotic analgesics takes place on specific opiate receptors of the peripheral ganglia.     

Action of narcotic analgesics and antagonists on spinal units responding to natural stimulation in the cat.

Morphine and morphine-related agents were applied by microiontophoresis in the lumbar spinal cord of spinal cats to single units classified on the basis of their responses to natural cutaneous or proprioceptive stimulation. Opiate application had a current-dependent depressant effect on the ongoing activities of about one-third of the units tested. This effect was observed in laminae I and IV--VI, but only with units responding to noxious cutaneous stimuli: the nociceptive responses were themselves depressed. Excitatory and inhibitory responses to glutamate and gamma-aminobutyric acid, respectively, were also depressed. Intravenous administration of the opiates at doses reported to produce analgesia in the cat also depressed only units responding to noxious cutaneous stimuli, including their nociceptive responses. This depression could be reversed by either the iontophoretic application (100 nA) or the intravenous administration (0.1--0.8 mg/kg) of naloxone. These results are interpreted as further evidence that the analgesic effects of opiates are at least partly due to an action at the spinal level.     

Ionization constants and solubility of compounds involved in enzymatic synthesis of aminopenicillins and aminocephalosporins

The article deals with experimental determination of ionization constants and solubility for the compounds (target products, initial β-lactams, acylating agents and by-products) involved in enzymatic synthesis of some therapeutically used aminopenicillins and aminocephalosporins, namely ampicillin, amoxicillin, cephalexin, cephadroxil, cephaloglycin, cefaclor, cefprozil, cefatrizine. Methodology of investigations and the evaluation of experimental data for the determination of ionization constants and solubility of the different type electrolytes are presented. Applications of the methods based on acid–base potentiometric titration and on determination of solubility–pH dependence of assayed substances are discussed. The original data on ionization constants and solubility of amoxicillin, cefprozil, cefatrizine, cephadroxil and initial β-lactams for production of cefaclor, cefprozil and cefatrizine, as well as solubility of by-product d-(−)-p-hydroxyphenylglycine are presented. Experimentally determined parameters and constants available in the literature for all abovementioned aminopenicillins and aminocephalosporins are collected. These data might be used for choice of the conditions of both processes: the enzymatic synthesis and the isolation of the product from reaction mixture.